Angiogenesis is a process of sprouting into a new vessel from an existing vessel. This process is associated with the migration and proliferation of vascular endothelial cell. Angiogenesis is relative to many serious human diseases, such as malignant tumor. So far, it was found that ocular angiogenesis diseases comprise age-related macular degeneration (AMD), diabetic retinopathy, neovascular glaucoma, and so on. The common characteristic of these diseases lies in the abnormal proliferation of ocular angiogenesis (Xiao Jin, et al., “Research Progress on the Clinical Application and Basic Mechanism of Anti-VEGF Drug”, CHINA FOREIGN MEDICAL TREATMENT, 2012).
Macular degeneration is mainly divided into two types, dry and wet, wherein wet macular degeneration (AMD) is characterized by new vessel of choroid entering the retina and the subsequent pathological changes such as bleeding, exudation and edema. Wet macular degeneration will cause a rapid loss of vision, which is more serious than dry macular degeneration. Currently, there is a good progress in the treatment of wet macular degeneration. The early laser-cauterizing hemostasis is replaced by VEGF antagonists, however, the later is replaced by photodynamic therapy soon due to the poor effect. Although photodynamic therapy has an improved efficacy, it is still unsatisfactory. Recently, a new VEGF antagonist—Lucentis, which is a recombinant of human-derived VEGF subtype monoclonal antibody fragment, is developed and it could reduce angiogenesis. This medicament is approved by U.S. FDA for treating wet macular degeneration in 2006, which has a good efficacy; and meanwhile, it was found that this anti-VEGF drug also has therapeutic effect on diabetic retinopathy and neovascular glaucoma. However, since Lucentis is an antibody drug with an extremely high price, it cannot popularize all over the world. Therefore, it is an intense competition focus in the current international pharmaceutical industry to develop small molecular angiogenesis inhibitor medicament having excellent efficacy and low price.
Protein kinase is also known as protein phosphakinase, which is an enzyme for catalyzing protein phosphorylation. Protein kinase could transfer Î3-phosphoric acid in adenosine triphosphoric acid (ATP) to the amino acid residue of a protein molecule, for example, to the hydroxy in certain serine, threonine or tyrosine residues, thereby to change the conformation and activity of the protein and enzyme. Protein phosphorylation is important for various signal transduction pathways, and most of the important intracellular life activity processes cannot do without protein phosphorylation.
Protein kinases are divided into five classes: protein serine/threonine kinases, protein tyrosine kinases, protein histidine kinases, protein tryptophan kinases and protein aspartyl/glutamoyl kinases. Protein kinases play an important role in the regulation and maintenance of cell processes. An abnormal kinase activity is observed in many disease states, comprising malignant tumors, immune diseases, cardiovascular diseases, diabetes, infectious diseases, arthritis and other immunologic derangement, nervous system diseases such as senile dementia, Alzheimer's disease (AD) and so on. It has been found that over 400 human diseases are associated with protein kinases.
VEGFR (Vascular Endothelial Cell Growth Factor Receptor) family members are receptor tyrosine kinases, e.g., VEGFR1, VEGFR2 and so on. These receptors play an important role in the growth and metastasis of malignant tumors as well as in the development process of diseases such as vascular proliferative diseases (e.g., macular degeneration and tumor). PDGFR (Platelet-Derived Growth Factor Receptor) family members are receptor tyrosine kinases, e.g., PDGFRα and PDGFRβ, and colony-stimulating factor-1 receptor, stem cell growth factor receptor KIT, and so on. It was found that these kinases are closely associated with the occurrence and development of tumors. The abnormal expression of PDGFR has been found in melanoma, meningeoma, neuroendocrine neoplasm, ovarian cancer, prostate cancer, lung cancer and pancreatic cancer. The abnormal activation of KIT is a direct inducement of the occurrence and development of many tumors.
FGFR (Fibroblast Growth Factor Receptor) family members comprise FGFR1, FGFR2 and so on, which are closely associated with cancers. For example, the abnormal activation of FGFR2 has been found in endometrial cancer, cervical cancer, breast cancer, lung cancer and stomach cancer. SRC kinase family comprises proteins having tyrosine protein kinase activity. SRC kinase family, as an oncegene protein, is initially found in Rous Sarcoma Virus. It has been found that the inhibition of SRC has some treatment and improvement effect on cancers or other diseases. p38 Mitogen-Activated Protein Kinase (MAPK) Pathway is intracellular stress response signal pathway, which is closely associated with inflammatory response. Therefore, there is still a need to develop new protein kinase inhibitors.